Researchers Using Models To Understand COVID-19, Other News

August 7, 2020

August 7, 2020 | Researchers are continuing to analyze COVID-19 through several models. A new mouse model is being developed in China to test and confirm the efficacy of a potential vaccine, while a researcher in the US is using computer models to understand the structure of the virus.

Literature Updates

Researchers in China have developed a new mouse model of COVID-19 infection that may help facilitate testing of vaccines and therapeutics. The model, which has been used to test and confirm the protective efficacy of a COVID-19 vaccine candidate, is described in a recent article published in Science. Efforts to study virus infection and evaluate vaccines in mice have up to now required mice to be engineered to express human ACE2. This represents a new approach where a strain of SARS-CoV-2 seen in the clinic is adapted in the mouse respiratory tract to develop a mutant version that was able to replicate and cause disease in young and aged mice; both groups showed pneumonia and inflammatory responses after intranasal infection, clinical features seen in human patients. DOI: 10.1126/science.abc4730

In an article in Research Ideas and Outcomes, a researcher at The Catholic University of America (Washington, D.C.) details how he has used computer models to understand the structure of the SARS-CoV-2 virus on the molecular level and try to figure out how the virus functions. It describes how antibodies found in the first SARS outbreak in 2002 (80R and m396) were reengineered to fit the new virus using computer simulation, and points to the discovery that sequence differences prevent 80R and m396 from binding to COVID-19—which could pave the way to engineering new antibodies that are effective. Docking experiments utilizing supercomputers at the Texas Advanced Computing Center and Pittsburgh Supercomputer Center showed that amino acid substitutions in 80R and m396 should increase binding interactions between the antibodies and SARS-CoV-2. The in-silico analysis could fast-track passive immunity that could prevent infection for several months. DOI: 10.3897/rio.6.e55281

Researchers at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences have used X-ray crystallography to determine and analyze the precise structure of the complex of the Nsp16 and Nsp10 coronavirus proteins. They report in Nature Communications that they’ve identified a deep canyon on the surface of the protein complex where binding of the viral RNA occurs, and a “cap” is installed. A cap is a special structure of SARS-CoV-2 that allows the virus to infect the human body and multiply within it. Targeting the canyon by inhibitors that suppress the activity of the Nsp16 and Nsp10 protein complex may, in the future, serve as drugs to combat many coronaviruses. DOI: 10.1038/s41467-020-17495-9

Researchers from the Perelman School of Medicine at the University of Pennsylvania have identified a protein called histone deacetylase 3 (HDAC3) as the orchestrator of the immune system's inflammation response to infection. This has implications for COVID-19 as well as other diseases such as cancer, heart disease and diabetes where the rise-and-fall in inflammatory factors go unchecked. Using both specially cultured cells and small animal models, HDAC3 was found to be directly involved in the production of agents that help kill off harmful pathogens as well as the restoration of homeostasis. Their work, published in Nature, shows that some of the methods being tested to fight harmful inflammation that target molecules like HDAC3 could have unintended and deadly consequences. The non-enzymatic functions of HDAC3, which have been previously under-appreciated, are responsible for the production of cytokine storm—a highly lethal phenomenon widely reported in patients infected with COVID-19. DOI: 10.1038/s41586-020-2576-2

Virologists in the College of Veterinary Medicine at Kansas State University have published a study in Science Translational Medicine showing a possible therapeutic treatment for COVID-19. It reveals how small molecule protease inhibitors show potency against human coronaviruses, including SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV). These coronavirus 3C-like proteases (aka 3CLpro) are strong therapeutic targets, they say, because they play vital roles in coronavirus replication. In their study, optimized coronavirus 3CLpro inhibitors blocked replication of the human coronaviruses MERS-CoV and SARS-CoV-2 in cultured cells and in a mouse model for MERS. Co-collaborators on the research are at Wichita State University, the University of Iowa and the University of Kansas. DOI: 10.1126/scitranslmed.abc5332

Brazilian researchers have shown that artificial intelligence can increase the effectiveness of drug repositioning or repurposing research for psychiatric and neurological disorders, and the novel drug screening approach will now be used in another study with the aim of repurposing drugs to treat COVID-19. In a study published back in May in Translational Psychiatry, they correlated information on genes associated with these disorders and drugs approved for use in treating other diseases that might potentially inhibit or activate these genes. That study identified 63 drugs targeting 31 genes and potential candidates for testing against Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, bipolar disorder, schizophrenia and autism. A total of 1,588 genes were correlated with 722 drugs. They used a machine learning approach known as network medicine—an emerging field that combines systems biology and network science to understand how genes interact in disease and health—to investigate the molecular characteristics and mechanisms of the psychiatric and neurological disorders. The group used IBM Watson for Drug Discovery as well as programs developed in their own laboratory to mine information in more than 20 million scientific articles published over the last 50 years. DOI: 10.1038/s41398-020-0827-5

One of the immune system's oldest branches, called complement, may be influencing the severity of COVID disease, according to researchers at Columbia University Irving Medical Center. Among other findings linking complement to COVID, the researchers found that people with age-related macular degeneration—a disorder caused by overactive complement—are at greater risk of developing severe complications and dying from COVID. The connection with complement suggests that existing drugs that inhibit the complement system could help treat patients with severe disease. The study published in Nature Medicine. The authors also found evidence that clotting activity is linked to COVID severity and that mutations in certain complement and coagulation genes are associated with hospitalization of COVID patients. Findings stem from an earlier finding that coronaviruses are masters of viral mimicry, particularly with proteins involved in coagulation and proteins that make up complement. DOI: 10.1038/s41591-020-1021-2

SARS-CoV-2 presents at least six strains and, despite its mutations, shows little variability (approximately seven mutations per sample, less than half that of common influenza)—good news for the researchers working on a viable vaccine, which was shared by scientists at the University of Bologna (Italy) in Frontiers in Microbiology. Results drew from an analysis of 48,635 coronavirus genomes that were isolated by researchers in labs across the world. They then mapped the spread and mutations of the virus during its journey to all continents. Treatments under development, including a vaccine, might be effective against all the virus strains, the authors conclude. DOI: /10.3389/fmicb.2020.01800

Researchers affiliated with the Optics and Photonics Research Center (Brazil) advocate for photodynamic therapy to combat secondary infections in COVID-19 patients in an article published in Photodiagnosis and Photodynamic Therapy. The technique combines light and a photosensitizing chemical substance to kill microorganisms in the respiratory tract. The compounds interact with light to produce a highly reactive oxygen species that kills viruses and bacteria by oxidizing their membranes. When the patient inhales these substances, the drug can be activated with extracorporeal light, which then attacks pathogens in the airways. Photodynamic therapy cannot be used to attack SARS-CoV-2 directly but it can be used as a treatment for COVID-19 coinfections caused by bacteria and other viruses, they argue. Several studies have already been conducted on the use of photodynamic therapy to treat pneumonia, skin cancer, and other diseases, and a new study is about to begin in partnership with researchers at the University of Toronto in Canada that will evaluate its use in cases of pneumonia in pigs. DOI: 10.1016/j.pdpdt.2020.101804

Luring SARS-CoV-2 with a decoy—an engineered, fee-floating receptor protein—binds the virus and blocks infection, suggests a study published in Science. Administering a decoy based on ACE2, the receptor protein on the surface of the cell to which the coronavirus binds, might neutralize infection as well as rescue lost ACE2 activity and directly treat aspects of COVID-19, the researchers say. As a potential therapeutic agent, a decoy receptor would have an advantage over other drugs because to evade it the virus would have to mutate in a way that makes it less infectious. The decoy, unlike ACE2, would be optimized for the binding role. After examining more than 2,000 ACE2 mutations and creating cells with the mutant receptors on their surfaces, researchers found a combination of three mutations that created a receptor that bound to the virus 50 times more strongly. They then made a soluble version of the engineered receptor. The strong affinity between the virus and the decoy receptor—rivaling the best antibodies identified to date—has been verified by the U.S. Army Medical Research Institute of Infectious Diseases as well as at the University of Illinois. The decoy receptor is now being tested in mice and exploring how it bonds to other coronaviruses with potential to become future pandemics if they cross from bats to humans. DOI: 10.1126/science.abc0870

In another study published in Science, scientists show that memory helper T cells that recognize common cold coronaviruses also recognize matching sites on SARS-CoV-2. That may explain why some people have milder COVID-19 cases than others, they speculate. Immune reactivity may translate to different degrees of protection, with those having a strong T cell response afforded the opportunity to mount a much quicker and better response. The work builds on previous reports from around the globe that many people never exposed to SARS-CoV-2 had T cells that reacted to the virus. For this study, researchers found that unexposed individuals can produce a range of memory T cells that are equally reactive against SARS-CoV-2 and four types of common cold coronaviruses. They additionally found that pre-existing immune memory was directed not only at the SARS-CoV-2's spike protein, which most vaccine candidates are targeting, but also other SARS-CoV-2 proteins. It might therefore be possible to take advantage of this cross-reactivity with multiple viral targets to further enhance vaccine potency. DOI: 10.1126/science.abd3871

Researchers at Yale University School of Medicine have developed a new mouse model to study SARS-CoV-2 infection and disease, aiding in the discovery that key antiviral signaling proteins may not protect the lungs but rather cause much of the tissue damage associated with COVID-19. To create their alternative mouse model, the animals were first infected with a different, harmless virus carrying the human ACE2 gene that enabled the SARS-CoV-2 to replicate and induced an inflammatory response like that observed in COVID-19 patients. The infected mice also rapidly developed neutralizing antibodies against SARS-CoV-2. When the mice lacking the key components of the type I interferon pathway were infected, they were no worse at controlling SARS-CoV-2 infection, but they also recruited fewer inflammatory immune cells into their lungs. This indicates that type I interferons—currently being used as a treatment for COVID-19—don’t restrict SARS-CoV-2 replication and may play a pathological role in COVID-19 respiratory inflammation. The early timing of interferon-based treatment will be important for it to provide protection and benefit, they say. Results published in the Journal of Experimental Medicine. DOI: 10.1084/jem.20201241

Genes thought to play a role in how the SARS-CoV-2 virus infects human cells are active in embryos as early as the second week of pregnancy, say scientists at the University of Cambridge and the California Institute of Technology. The researchers say this could mean embryos are susceptible to COVID-19 if the mother gets sick, potentially affecting the chances of a successful pregnancy. To examine the risks, they cultured human embryos through the stage they normally implant in the body of the mother to look at the expression of key genes. Findings included patterns of expression of ACE2 (providing the genetic code for the SARS-CoV-2 receptor) and TMPRSS2 (providing the code for a molecule that cleaves both the viral spike protein and the ACE2 receptor), allowing infection to occur. These genes were expressed during key stages of the embryo's development, and in parts of the embryo that go on to develop into tissues that interact with the maternal blood supply for nutrient exchange. The study, published in Open Biology, reports the finding of the RNA messengers. Researchers emphasize the importance of women planning for a family to try to reduce their risk of infection. DOI: 10.1098/rsob.200162

Initial data from mice suggest that SARS-CoV-2 might not be targeting taste buds, as has been suspected due to reports of some COVID-19 patients losing their sense of smell and/or taste. University of Georgia researchers report in ACS Pharmacology & Translational Science that they found ACE2 (a receptor on the surface of some cells, including those of the human tongue) was enriched in cells that give the tongue its rough surface, but couldn't be found in most taste bud cells. That means the virus probably doesn’t cause taste loss through direct infection of these cells. Instead, taste buds might be damaged by inflammation caused by the infection. They also showed that other viruses that affect taste, including the flu virus, might affect different tongue cell types. Based on an analysis of mice at different developmental stages and previous studies in humans, it also appears possible that fetuses have distinct susceptibilities to SARS-CoV-2 infection at different stages. DOI: 10.1021/acsptsci.0c00062

The latest paper about the Moderna-NIH vaccine mRNA-1273 that recently entered phase 3 human trials published in Nature, describing both preclinical results and the carefully engineered spike protein that mimics the infection-spreading part of the SARS-CoV-2 virus. The investigational vaccine induced neutralizing antibodies in mice when given as two intramuscular injections of a 1-microgram (mcg) dose three weeks apart; mice given two injections of the 1-mcg dose and later challenged with SARS-CoV-2 virus either five or 13 weeks after the second injection were protected from viral replication in the lungs and nose. Importantly, mice challenged seven weeks after only a single dose of 1 mcg or 10 mcg of mRNA-1273 were protected against viral replication in the lung. The investigational vaccine also induced robust CD8 T-cell responses. Years of earlier research into coronaviruses was critical for the fastest-ever progression (66 days) from virus genome sequencing to vaccine testing in humans. The spike protein is a shapeshifter, changing its structure before and after fusing with cells. The immune system responds best when the spike protein is in its prefusion shape, so researchers reengineered the protein in two key places to lock it into that shape. Using small genetic modifications to the gene sequence that encodes for the protein, they essentially made part of the spring-loaded portion of the molecule more rigid—the same tactic successfully used back in 2017 to stabilize the shape-shifting spike protein for MERS-CoV. The protein engineering work was led by a team at The University of Texas at Austin. Other collaborating institutions on the preclinical work were the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center in Nashville. DOI: /10.1038/s41586-020-2622-0

A team of chemists from HSE University and the Zelinsky Institute of Organic Chemistry (Russia) used molecular modelling to find out that two well-known medications—disulfiram (for alcoholism) and neratinib (experimental drug for breast cancer)—can be used to fight SARS-CoV-2, as reported in Mendeleev Communications. The classical docking process used for molecular modeling doesn’t work in SARS-CoV-2, so they instead used an “on-top docking” method that they invented shortly before the pandemic. It involved investigating the entire surface of the Mpro target protein with many medications and hoping big calculation powers would return useful dockings. The potential drugs were taken from a database of FDA-approved medications and the research team's own algorithms were used for modelling. In tests performed at Reaction Biology Corp., a certified laboratory in the U.S., both disulfiram and neratinib were found to inhibit Mpro, although the latter was deemed insufficient for clinical use. The main achievement is demonstration of the new on-top docking approach in returning realistic and controllable results. DOI: 10.1016/j.mencom.2020.07.004

In Molecular Systems Biology, researchers at Uppsala University (Sweden) have described the presence of angiotensin I converting enzyme 2 (ACE2)—thought to be the key protein used by the SARS-CoV-2 virus for host cell entry and development of COVID-19—throughout the human body. In contrast to previous studies, theirs shows that no or very little ACE2 protein is present in the normal respiratory system. The article presents a large-scale, systematic evaluation of ACE2 expression in more than 150 cell types, at both messenger RNA (mRNA) and protein levels. The fact that ACE2 has limited expression in respiratory epithelial cells highlights the need for further study of the biological mechanisms responsible for COVID-19 infection and disease progression, they say. The expression profiles in previous studies indicating that ACE2 is highly expressed in the human lung have not been reliably presented along with tissues and organs from the entire human body or based on several different datasets at mRNA and protein levels. For this study, immunohistochemical analysis of 360 normal lung samples from an extended patient cohort was based on the Human Protein Atlas resource. Two different antibodies, which were stringently validated, were used. DOI: 10.15252/msb.20209610

Industry Updates

Oxford Nanopore launched its novel LamPORE SARS-CoV-2 test and announced an agreement with the UK’s Department of Health and Social Care, to make an initial 450,000 LamPORE tests available for use by a number of NHS testing laboratories. As well as providing a large number of tests for existing labs, the program will help the UK to understand the different use cases for the technology, for example the potential asymptomatic screening of frontline staff. Because of its scalability, LamPORE has the potential to provide both large-scale screening to detect the virus in broader populations, and rapid, focused, localized analysis. LamPORE is designed to be deployed on Oxford Nanopore’s desktop device (GridION) or palm-sized device (MinION Mk1C), providing the capacity of processing up to 15,000 saliva or swab RNA samples a day or 2,000 samples a day respectively. It is well suited to use in a central laboratory for high-throughput sample processing, or near-community ‘pop-up lab’. LamPORE results can be generated in under two hours. Oxford Nanopore is currently also developing LamPORE to test for multiple pathogens within a single sample, including influenza A (H1N1 and H3N2), influenza B, respiratory syncytial virus (RSV) and SARS-CoV-2. This is intended to allow healthcare professionals to distinguish between these infections, better manage expected winter pressures on the NHS and guide public health and clinical management of these diseases at a time of traditionally heightened pressure on health services. Press release.

The AI-powered nonprofit startup Reboot Rx has launched the Reboot: COVID-Cancer Project, a free, publicly accessible resource for researchers and physicians to quickly find and review data on COVID-19 and cancer. Cancer patients are among those with the highest risk of dying from COVID-19. From over 170,000 published studies and registered clinical trials, Reboot Rx has identified the 850 that are most relevant for cancer patients with COVID-19. The Reboot: COVID-Cancer Project provides crucial insights into treatment responses and mortality rates to understand how cancer patients are uniquely vulnerable to COVID-19. Through this effort, Reboot Rx is helping researchers and physicians pursue the most effective treatments. Press release.

Thermo Fisher Scientific has launched a new, highly automated, real-time PCR solution designed to analyze up to 6,000 samples in a single day to meet increasing global demand for COVID-19 testing. The Thermo Fisher Scientific Amplitude Solution is a molecular diagnostic testing system that leverages the company's Applied Biosystems QuantStudio 7 Flex Real-time PCR instruments along with liquid handling products from Tecan Group, a global leader in laboratory automation and liquid handling. The modular solution delivers test results in a four-step process requiring minimal hands-on time, laboratory space and staffing resources. The Amplitude Solution utilizes Thermo Fisher's Applied Biosystems TaqPath COVID-19 Combo Kit, a fast, highly sensitive multiplex diagnostic test that contains the assays and controls needed for the qualitative detection of nucleic acid from SARS-CoV-2, the virus that causes COVID-19. The company will submit this new end-to-end solution to the U.S. Food and Drug Administration for Emergency Use Authorization (EUA) and plans to secure additional authorizations globally. Press release.

P33, Open Commons Consortium (OCC) and MATTER have launched the Chicagoland COVID-19 Data Commons (CCC), a centralized data platform created in partnership with regional healthcare providers, to help clinicians, researchers and community advocates understand how the disease behaves within the Chicagoland population. P33, a private-sector led initiative promoting inclusive tech growth in Chicagoland; the OCC, a builder of data commons and data-sharing ecosystems; and MATTER, healthcare startup incubator, partnered to create the Chicagoland COVID-19 Data Commons to understand the pandemic, measure Chicagoland's regional response and build a helpful decision-making tool for local government. COVID-19 has already had a devastating impact on our communities. In Chicago, there have been almost 60,000+ cases of COVID-19 identified residents and almost 140,000+ in Illinois. The impact has been particularly hard on black and Latinx communities. The OCC, MATTER and P33 are engaging hospitals and nonprofits in Chicagoland that are serving patients impacted by the disparities of COVID to include their clinical data in the CCC, ensuring accurate representation of the data across all zip codes in Chicago. Participating health systems and hospitals include Rush University Hospital, University of Chicago, University of Illinois Chicago, St Anthony Hospital, Sinai Health System, Medical Home Network, NorthShore University Health Systems, Community Health, and Illinois Association of Free and Charitable Clinics. Press release.